An understanding of the neurobiological basis of learning and memory is one of the most important problems in modern neuroscience. At present there are several model organisms that are used to study learning and memory. No one organism, however, currently combines rapid embryological development, suitability for forwards and reverse genetic manipulation, electrophysiological tractability and a vertebrate genome and nervous system. The purpose of this proposal is to develop the zebrafish into a useful model organism for a cell biological analysis of learning and memory. The zebrafish has several advantages as a model organism for the study of learning and memory. It is suitable for both forwards and reverse genetics. In addition, the zebrafish possesses a simple reflexive escape response, the C-start, which is mediated by a relatively simple neural circuit in the fish's hindbrain and spinal cord. Many neurons within this circuit have already been identified and electrophysiologically recorded from. The C-start reflex will be used to investigate the genetic basis of simple forms of nonassociative and associative memory, including habituation, dishabituation, sensitization and classical conditioning. Both short-term and long-term learning protocols will be developed. Another major goal will be to develop reverse genetic tools for identifying genes that are important for learning and memory in the zebrafish. Toward this end a methodology for disrupting the expression of specific genes (gene knockdown) using RNA interference (RNAi) will be developed. In addition, a computational screen will be developed to identify learning-associated genes in the zebrafish. Such genes will then become targets for gene knockdown in studies of learning and memory. It is expected that the findings from this study will speed the development of the zebrafish into a model organism for memory studies. In addition, the results from the proposed experiments will contribute to a fundamental understanding of the processes that underlie learning and memory. Such an understanding will facilitate the development of treatments for Alzheimer's disease and other disorders of memory. [unreadable] [unreadable] [unreadable]